Melanin concentrating hormone (MCH) is a cyclic 19-amino acid polypeptide, which is mainly produced by hypothalamic neurons projecting widely throughout the central nervous system (CNS) (J. Comp. Neurol. (1992) 319, 218-245). MCH mediates its effects through two G protein-coupled receptors (GPCRS) termed MCH-1 and MCH-2 (reviewed in Doggrell, 2003). While in rodents only the MCH-1 receptor is expressed, human and primates express both MCH-1 and MCH-2 receptors (Genomics (2002), 79, 785-792). Originally, the MCH-1 receptor was considered a valuable target for the treatment of obesity as MCH promotes feeding behaviour in rodents (Nature (1996), 380, 243-247). Recently however, it was shown that MCH-1 antagonism produces anxiolytic and antidepressant profiles in rodents (Nat. Med. (2002) 8, 825-830; Neuropharmacology (2004), 46, 457-467; Neuropsychopharmacology (2006), 31(1), 112-120; Neuropsychopharmacology (2006), 31(6), 1135-1145). Thus, it is currently generally accepted that MCH receptors, particularly the MCH-1 receptor, are a good target for the treatment of affective spectrum disorders (Eur. J. Neuroscience (2000) 12, 1194-1216).
MCH-1 receptor mRNA and protein are distributed in various hypothalamic nuclei including the paraventricular nucleus and several limbic structures all implicated in the regulation of emotion and stress (Eur. J. Neuroscience (2000) 12, 1194-1216). In addition, dense labelling is detected in the nucleus accumbens shell (J. Comp. Neurol. (2001) 435, 26-40). Injection of MCH directly into the paraventricular nucleus has been found to increase plasma adrenocorticotropic hormone (ACTH) and to alter sleep architecture (Verret et al. 2003, BMC Neurosci 4:19). MCH also induces corticotrophin-releasing factor (CRF) release from hypothalamic explants, an effect that is sensitive to blockade by an MCH-1 receptor antagonist (J. Neuroendrocrinol. (2003) 15, 268-2729). Thus it seems likely that stimulation of MCH-1 receptor causes activation of the hypothalamus-pituitary-adrenal (HPA) axis through increases in CRF release. Injection of MCH into the nucleus accumbens shell, in which MCH-1 receptor is abundant, increased immobility in a forced swim test in rats, suggesting increased depressive behaviour (Soc. Neurosci. Abstr. (2004) 763.9). Moreover, Borowsky et al. (Nat. Med. (2002) 8, 825-830) reported the MCH-1 antagonist, SNAP-7941, exhibited antidepressant- and axiolytic-like affects in rodents tests, supporting a role for MCH-1 receptor in depression and anxiety.